An Association Study of Early Arsenic Exposure and Genes Related to Arsenic Metabolic Capacity on the Risk of Cardiovascular Disease (I)

Several studies reported that incidence of vascular and heart disease increased in human populations exposed to arsenic from environmental sources. Recently, it has been reported that low-level exposure to arsenic during development is toxic to heart formation and function in a mouse model. Mounting evidence suggests that exposure to arsenic leads to the cardiovascular diseases (CVD), but data from prospective cohort study about the long-lasting effects of early-life arsenic exposure during childhood on lifetime CVD are scarce. Methylation is the primary metabolic pathway of inorganic arsenic in humans. The relative distribution of arsenic metabolites in urine reflects arsenic methylation capacity and varies between individuals. It has been reported that N-6 adenine-specific DNA methyltransferase (N6AMT1), arsenite (+3 oxidation state) methyltransferase, (As3MT), omega isoform of glutathione S-transferase (GSTO), purine nucleoside phosphorylase (PNP), polynucleotide phosphorylase and mitochondrial ATP synthase are related to arsenic metabolic pathway. Therefore, early arsenic exposure on the risk of CVD as well as the impact of arsenic metabolic capacity on CVD need to be further clarified. About 4500 of long-term follow-up cohort subjects from home-visit interview in Lanyang Basin between 2011-2014 will be recruited in this study. Information from a structured questionnaire containing environmental risk factors, disease histories, and lifestyle will be used to adjust the confounding factors. Arsenic methylation capacity will be determined by the relative distribution of arsenic metabolites in urine. DNA from the cells of saliva will be used to identify novel variants on the genes related to arsenic metabolic pathway using next generation sequencing. Novel variants validation and association study of arsenic metabolic related genes with the risk of CVD will be genotyping by MassARRAY® iPLEX Gold-SNP Genotyping system Disease status of CVD will be confirmed through linkage with NIH database and National Death Registry. The aims of this project will be : (1) To discover novel variants on the genes related to arsenic metabolic pathway; (2) To validate the relationship between novel genetic variants of N6AMT1, As3MT, GSTO, PNP, polynucleotide phosphorylase, mitochondrial ATP synthase, and arsenic methylation capacity; (3) To investigate the association of early-life arsenic exposure with the risk of CVD and CVD risk factors (such as atherosclerosis, diabetes mellitus, hyperlipidemia, and hypertensive disease) between early-life and late-life arsenic exposure; (4) To investigate the interaction between environment factors (early-life arsenic exposure, dose of arsenic exposure) and arsenic metabolic related genes or gene-gene interaction on the risk of CVD; (5) To investigate the modify effect of arsenic metabolic related genes on the environment factors (early-life arsenic exposure, dose of arsenic exposure) for the risk of CVD.